title: The CYP2C19*17 variant is not independently associated with clopidogrel response.
abstract: BACKGROUND
  Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively.
  
  
  OBJECTIVE
  We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD).
  
  
  METHODS
  We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5'-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure.
  
  
  RESULTS
  The CYP2C19*2 and CYP2C19*17 variants were in LD (|D'| = 1.0; r(2)  = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (β = -5.24, P = 3.0 × 10(-9) and β = -5.36, P = 3.3 × 10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (β = 7.55, P = 2.9 × 10(-16) and β = 7.51, P = 7.0 × 10(-15) , respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (β = 1.57, P = 0.04 and β = -1.98, P = 0.01, respectively) but not after (β = 0.40, P = 0.59 and β = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response.
  
  
  CONCLUSIONS
  Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition and Program in Personalized and Genomic Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Lewis
authors.forename: S H
authors.initials: SH
authors.lastname: Stephens
authors.forename: R B
authors.initials: RB
authors.lastname: Horenstein
authors.forename: J R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: K
authors.initials: K
authors.lastname: Ryan
authors.forename: C J
authors.initials: CJ
authors.lastname: Peer
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: S D
authors.initials: SD
authors.lastname: Spencer
authors.forename: M A
authors.initials: MA
authors.lastname: Pacanowski
authors.forename: B D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: A R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19-related; Clopidogrel; drug metabolism; linkage disequilibrium; pharmacogenetics; platelets; poor